Through the predecessor to this application (R01DE019456) we have been evaluating an underserved population of African-Americans in two health departments in North-Florida, diagnosed with an uncommon, aggressive form of periodontal disease known as localized aggressive periodontitis (LAP). Despite its low prevalence, we have compiled data from a cohort of over 100 LAP subjects, amongst a population which lacks specialized dental care for this disease. Specifically, we have discovered a TLR-induced hyper-inflammatory response in these subjects, which correlates with disease presentation and systemic levels of endotoxin. Importantly, this hyper-responsiveness is also observed in some periodontally healthy siblings of LAP subjects, indicating a potential genetically acquired and/or regulated predisposition for disease in these individuals. Therefore, the goal of this proposal is to expand on our discoveries and investigate inherited genetic contributions to regulation of inflammatory signaling involved in, and epigenetic regulation of thi TLR-induced hyper-inflammatory response under the condition of LAP. Importantly, association of these factors with treatment response and long-term stability will also be determined. Specifically, we will be expanding our clinical centers to recruit new subjects to reach a total of 200 LAP cases, 200 age-matched healthy siblings of LAP subjects and 200 unrelated healthy controls, African- Americans, aged 5-25 years old, and systemically healthy. We will and perform clinical examination and collect peripheral blood from all subjects to specifically reach these 3 aims: 1- Evaluate specific toll-like receptor (TLR) and cytokine Single Nucleotide Polymorphisms (SNPs) associated with hyper-inflammatory profile in LAP; 2- Delineate the signaling events associated with TLR-induced hyper-responsiveness in LAP; and 3- Examine the role of diverse epigenetic modifications in the regulation of TLR-induced hyper-responsiveness in LAP. Importantly, the effect of periodontal therapy on the observed phenomenon will also be evaluated. Evaluation of these mechanisms will not only lead to improved outcomes of periodontal therapy, but are imperative for the prevention of the cyclical nature of disease recurrence observed in LAP, as well as disease initiation in healthy susceptible individuals. Furthermore, understanding the mechanisms behind this aggressive inflammatory response has enormous implications in the future health of these children, as hyper- inflammation is also involved in other, systemic, diseases such as diabetes and cardiovascular disease. Importantly, results from this proposal will hopefully lead to novel diagnostic and therapeutic targets for the prevention and successful long-term management of LAP.